SummaryIn the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. Gugglesterone, a derivative of the resin of guggul tree Commiphora mukul has been widely reported as a hypolipidemic agent and more recently as an inhibitor of NF-kB activation. It was found that gugglesterone inhibited radiation-induced NF-kB activation and enhanced radiosensitivity in the pancreatic cell line, PC-Sw. Gugglesterone reduced both cell cycle movement and cell growth and reduced ER alpha protein in MCF7 cells and IGF1-R beta protein in colon cancer cells and pancreatic cancer cells and inhibited DNA double strand break (DSB) repair following radiation. With respect to normal tissue response to radiation, we found that keratinocyte growth factor (KGF) gene transfer to mouse submandibular glands afforded significant protection against both single and fractionated doses of radiation. Local gene transfer resulted in significant systemic levels of KGF; however, KGF gene transfer had no effect on tumor growth with or without radiation. These data suggest potential clinical application. We have also shown that the nitroxide, Tempol protects against radiation-induced oral mucositis (both systemic and topically applied). Oral mucositis is a common toxicity associated with the chemoradiation (cisplatin combined with fractionated radiation) treatment of head and neck cancers. Tempol also protects against chemoradiation-induced mucositis yet did not alter chemoradiation with respect to tumor regrowth delay, providing sufficient pre-clinical data to introduce Tempol into human radiation oncology clinical trials.Lastly, a novel 5-membered ring nitroxide (23c) was shown to be a potent protector against radiation-induced lethality in mice and studies are planned to determine if protection can be observed in selected normal tissues in mice, particularly the brain since the nitroxide penetrates the blood brain barrier.